Prostate cancer is a significant health problem. This year 180,000 men will likely be diagnosed with prostate cancer and some 32,000 men will likely die of this disease in this country alone. For the most part, prostate cancer patients are currently treated by surgery, radiation and hormonal therapy and have their best chance of living more than 3 - 5 years if their prostate cancer is detected early, if it has not invaded beyond the prostatic capsule and if there are no distant site metastases. However, there are few options for patients with advanced hormone refractory prostate cancer. The best hope we have for treating patients with advanced disease is to understand the molecular biology of such cancers, design sensitive and predictive detection schemes to identify those patients most at risk of developing progressive and aggressive disease, and implementing novel intervention modalities directed to specific molecular targets. To this end, the long-term objectives of these studies are (1) to test the central hypothesis that functional abrogation of the normal androgen signaling axis (ASX), specifically the androgen receptor (AR) and androgen receptor interacting proteins (ARIPs), during the natural history of prostate cancer provides a molecular basis for tumor progression leading to the emergence of an androgen independent phenotype (a process we term "androdysgenesis") and metastasis, (2) to identify the molecular mechanisms whereby deregulated ASX contributes to the initiation, progression, metastogenesis and androdysgenesis and (3) to identify and validate new molecular targets in the ASX for the development and deployment of efficacious intervention therapies. To further test our central hypothesis and establish a clear and causal relationship between AR variants and prostate cancer we propose the following: Specific Aim 1: To generate and characterize novel independent lines of transgenic mice harboring specific AR gene mutations under temporal and spatial control of the regulatory elements derived from the probasin gene. Specific Aim 2: To identify, isolate and characterize AR- and AR-variant specific interacting proteins that are differentially expressed throughout the natural history of prostate cancer in the autochthonous TRAMP model. Specific Aim 3: To characterize the molecular targets through which AR and AR-variants contribute to the initiation, progression, metastogenesis and androdysgenesis of prostate cancer.